This project is based on the assumption of heterogeneity of schizophrenia. Its objective is to classify schizophrenic patients using measures of sleep physiology and REM sleep phasic events such as middle ear muscle activity and to relate these measures to pharmacological response and CSF neurotransmitter biochemistry. In the next three years we plan to investigate the role of serotonin in schizophrenia and sleep physiology. In particular, we plan to study the relationship of serotonin to REM sleep MEMA and symptom clusters in both schizophrenia and schizoaffective disorder. We also plan to observe the effect of the serotonin agonist/depletor fenfluramine on REM phasic events, on clinical symptoms, and on serotonin as measured in whole blood and as the CSF metabolite 5-HIAA. We have two specific objectives. Our first objective is to replicate in a cross-sectional study our recent observation that REM MEMA is inversely related to CSF concentrations of 5-HIAA and to extend that finding by determining if REM MEMA rates also covary with blood serotonin levels. Our second objective involves a longitudinal study of the role of serotonin in schizophrenia and schizoaffective disorder. We plan to determine how changes in clinical symptoms, MEMA rate, CSF 5-HIAA levels, and blood serotonin levels covary when serotonin is manipulated by the drug fenfluramine. We will test the following hypotheses: i.) MEMA rate is inversely related to CSF 5-HIAA and blood 5-HT levels in schizophrenia and schizoaffective disorder; ii.) CSF 5-HIAA and blood 5-HT levels are positively related; iii.) hyperserotonemia is associated with low MEMA rates and negative symptom schizophrenia; iv.) fenfluramine will decrease with CSF 5-HIAA and blood 5-HT and the effect will be dose-related; v.) fenfluramine will increase REM sleep MEMA rate and this effect will also be dose-related; vi.) fenfluramine will be associated with a decrease in the negative symptoms of schizophrenia.